CD4+ T lymphocytes respond to foreign peptides presented in the context of major histocompatibility complex (MHC) class II molecules and play a critical role in most antiviral responses. In the conventional model, class ll-binding peptides are generated in the late endosome via unfojding and/or proteolysis and subsequently loaded onto class II molecules in the same compartment with the assistance of the H-2M heterodimer. In contrast, the conventional pathway for MHC class l-restricted presentation to CD8+ T cells entails delivery of antigen to the cytosol where it is digested by the proteasome. The resultant peptides are transported to the endoplasmic reticulum by the TAP heterodimer where they are loaded onto empty, nascent class I molecules. This dichotomy is a well established immunological tenet and has strongly influenced thinking in the field for many years. Recently we reported on two MHC class I l-restricted influenza epitopes that are presented via a pathway that is decidedly class l-like in that presentation depends upon cytosolic delivery, functional proteasome and the presence of TAP. Analysis of bulk class I l-restricted responses against influenza and vaccinia revealed that a substantial proportion is directed against proteasome-dependent epitopes. We have designed a research plan, a natural extension of our published studies, in order to 1) gain insight into the division of labor between the two class II pathways and 2) assess the degree to which proteasome-dependent CD4+ T cell responses shape the overall immune response and contribute to protection. Execution of the plan could fundamentally alter the general perception of CD4+ T cell responses and the roles they play in protection, thereby strongly influencing the design of future vaccines.